Abstract

We present a case of a 71-year-old male Chamorro patient from Guam who presented with progressive supranuclear palsy (PSP)-Richardson’s syndrome. Considering his strong family history of parkinsonism and a PSP phenotype, he was clinically diagnosed with Guam parkinsonism-dementia complex (PDC). Magnetic resonance imaging (MRI) of the brain revealed prominent midbrain atrophy with preserved pontine volume, forming the ‘hummingbird’ sign, which has not been described before in Guam PDC. Molecular analysis of the chromosome 9 open reading frame 72 gene (C9orf72) showed only 6 GGGGCC repeats. We discuss the clinico-pathological similarities and differences between PSP and Guam PDC, and highlight the topography of neuropathological changes seen in Guam PDC to explain the appearance of the ‘hummingbird’ sign on MRI.

Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a unique and seemingly familial neurodegenerative condition affecting the Chamorro people of Guam [1]. ALS affects younger patients while PDC occurs in later life [1]. Guam PDC usually presents with akinetic-rigid parkinsonism, occasionally with supranuclear gaze palsy akin to progressive supranuclear palsy (PSP) [1]. Few imaging studies have been conducted on Guam PDC patients [2,3], and despite their clinical similarities, there have been no reports of PSP-like features on brain magnetic resonance imaging (MRI) in patients with Guam PDC. Herein, we report a patient with Guam PDC whose MRI of the brain showed prominent midbrain atrophy with the ‘hummingbird’ sign.

CASE REPORT

A 71-year-old Chamorro male presented with worsening postural instability, gait freezing and frequent falls. He developed parkinsonism 5 years prior, characterized by bradykinesia, mild tremors and occasional falls. Along with motor deterioration, he also developed executive dysfunction with fluctuating short-term memory loss. His current medications included Sinemet (Carbidopa/Levodopa, 25 mg/250 mg) four times a day and Rivastigmine (1.5 mg twice a day).

Family history of the patient revealed parkinsonism in multiple family members (Figure 1). The patient was told that his paternal grandmother suffered from ‘Lytico-Bodig’, the Chamorro name for Guam ALS/PDC; however, he was not certain of the age of onset. His father developed parkinsonism in his late 40’s while his paternal uncles developed parkinsonism in their 50’s. The patient was not aware if his paternal cousins had parkinsonism. His sister has also developed parkinsonism characterized by limb slowness and gait difficulties.

Examination revealed a PSP-Richardson’s syndrome (Supplementary Video 1 in the Online-only Data Supplement). There was frontalis overactivity with reduced blink rate producing a ‘staring’ appearance. Neuro-ophthalmological examination showed impairment of down gaze, slowing of vertical and horizontal saccades and frequent saccadic intrusions. Parkinsonian features included symmetrical limb bradykinesia and rigidity, axial rigidity, and marked postural instability with frequent gait freezing. The applause sign was not consistently present. There were no apraxia, dysmetria, postural hypotension or Babinski signs observed. Motor response to dopaminergic medications was minimal. The Montreal Cognitive Assessment score was 16/30 with prominent deficits in visuospatial and executive functions as well as poor performance on delayed recall. In view of the strong family history of parkinsonism, together with clinical features mimicking PSP-Richardson’s syndrome, our clinical diagnosis was Guam PDC.

MRI of the brain of the patient. A: Mid sagittal T2-weighted imaging show prominent midbrain atrophy with preserved pontine volume, forming the silhouette of the head and body, respectively, of a hummingbird. Concavity of the superior midbrain profile is also present (arrow). B: Axial T2-weighted imaging show marked midbrain atrophy with concavity of the midbrain tegmentum (arrows). C: Coronal fluid-attenuated inversion recovery (FLAIR) imaging show marked right hippocampal atrophy with increased FLAIR signal (arrow), suggestive of mesial temporal sclerosis.

DISCUSSION

Despite the many clinical and neuropathological similarities between PSP and Guam PDC, there have been no reports of the ‘hummingbird’ sign on MRIs of the brain in Guam PDC. We believe that the radiological features seen in our patient correlates with the pathological findings of severe neuronal loss and high neurofibrillary tangle load in the midbrain, especially within the substantia nigra and ventral tegmental area of Guam PDC patients [5]. It is also demonstrated pathologically that only slight neuronal loss occurs within the pedunculopontine and pontine nuclei in Guam PDC, compatible with the preserved pontine volume seen in our patient [5]. A recent neuropathological study has shown that pathologically defined hippocampal sclerosis exists in Guam PDC patients, with some patients showing extensive scarring and severe neuronal loss with fibrillary gliosis in the cornu ammonis 1 area of the hippocampus [6]. We postulate that these pathological findings are likely to explain the right mesial temporal sclerosis observed on MRI in our patient. A brain volumetric study also showed preferential atrophy of the parahippocampal gyrus, hippocampus, temporal lobe, frontal lobe and basal ganglia-thalamic region in Guam PDC patients compared to asymptomatic Chamorros [2].

The clinical and histological similarities of Guam PDC and PSP were already observed in the 1960’s [1]. Both are considered tauopathies and show a similar topography of neurofibrillary degeneration in the subcortical and brainstem regions [1,5,7]. Some differences however, do exist between PSP and Guam PDC. PSP is a universal, sporadic disease and is almost never associated with ALS; Guam PDC is usually familial with frequent association with ALS, either within the same family or in the same individual [1]. The neurofibrillary tangles are also different; they are almost exclusively 4-repeat tau in PSP, while in Guam PDC, they are a mixture of 3-repeat and 4-repeat tau [7]. Finally, although Guam PDC is considered as a tauopathy, it has been demonstrated that the transactivation-responsive region DNA-binding protein (TDP)-43 is present in the brain and spinal cord of Guam ALS/PDC patients [6-8].

While it has been reported that polymorphisms in the microtubule-associated protein tau gene (MAPT) region increase the risk for Guam ALS/PDC, no pathogenic mutations in MAPT or other genes have been identified [9,10]. Expansion of the GGGGCC hexanucleotide repeat sequence in an intron of C9orf72 has been shown to cause autosomal dominant ALS and frontotemporal dementia, as well as in some cases of familial parkinsonism [9]. A study of familial ALS in the Kii Peninsula of Japan, a closely related condition having shared clinical and neuropathological features with Guam ALS/PDC, reported that 20% of these patients carry C9orf72 expansions [9]. In contrast, it is reported that Chamorro Guam ALS/PDC patients have normal copies ranging from 2 to 17, showing that C9orf72 expansions do not explain Guam ALS/PDC [9]. No pathogenic mutations in the LRRK2 gene were found in the same study. The 6 repeats of GGGGCC in C9orf72 in our patient is consistent with this observation.

Etiological hypotheses concerning beta-N-methylamino-L-alanine neurotoxicity via ingestion of cycad seeds and flying foxes have proved inconclusive and genetic studies have not found any causative genetic mutations [7,10]. With the decline in disease incidence, particularly that of the ALS phenotype [1], the cause of Guam ALS/PDC remains enigmatic.

Notes

Acknowledgements

We are very thankful to the patient and his family for providing valuable information and consenting to video publication.

We will also like to thank Dr Zhao Yi, Department of Clinical Research, Singapore General Hospital, for performing the molecular analysis of C9orf72. Louis CS Tan is supported by the Singapore National Research Foundation under its Translational and Clinical Research Flagship Programme (TCR12dec010) and administered by the Singapore Ministry of Health’s National Medical Research Council.

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